New Synthetic Procedure for 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers with Potent Antitumor Activity

Scebi Mkhize; Noriyuki Suzuki; Ayako Kurosawa; Makiko Fujinami; Chanya Chaicharoenpong; Tsutomu Ishikawa

doi:10.1055/s-0034-1378342

Synlett, Inhaltsverzeichnis

Synlett 2014; 25(14): 2059-2063
DOI: 10.1055/s-0034-1378342

letter

New Synthetic Procedure for 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers with Potent Antitumor Activity

Scebi Mkhize

Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan Fax: +81(43)2262919 eMail: n-suzuki@chiba-u.jp

,

Noriyuki Suzuki*

Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan Fax: +81(43)2262919 eMail: n-suzuki@chiba-u.jp

,

Ayako Kurosawa

Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan Fax: +81(43)2262919 eMail: n-suzuki@chiba-u.jp

,

Makiko Fujinami

Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan Fax: +81(43)2262919 eMail: n-suzuki@chiba-u.jp

,

Chanya Chaicharoenpong

Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan Fax: +81(43)2262919 eMail: n-suzuki@chiba-u.jp

,

Tsutomu Ishikawa*

Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan Fax: +81(43)2262919 eMail: n-suzuki@chiba-u.jp

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Abstract

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Abstract

1,4-Naphthoquinone 1-oxime methyl ethers carrying an ester-substituted aryl pendant at 2-position were concisely prepared as seed compounds with structural flexibility for structure–activity relationship studies on antitumor activity. The key synthetic intermediate was a phthalide–tetralone spiro compound, which was provided by palladium-coupling reaction between 2-bromobenzoate and 1-tetralone followed by OsO₄–NMO oxidation.

Key words

coupling reaction - oxidation - oxime - quinone - spiro compound

Volltext

Referenzen

References and Notes

1a Ishikawa T, Saito T, Ishii H. Tetrahedron 1995; 51: 8447
1b Watanabe T, Ohashi Y, Yoshino R, Komano N, Eguchi M, Maruyama S, Ishikawa T. Org. Biomol. Chem. 2003; 1: 3024

2a Ishikawa T, Saito T, Kurosawa A, Watanabe T, Maruyama S, Ichikawa Y.-I, Yamada R, Okuzawa H, Sato H, Ueno K. Chem. Pharm. Bull. 2011; 59: 472
2b Sato H, Yamada R, Yanagihara M, Okuzawa H, Iwata H, Kurosawa A, Ichinomiya S, Suzuki R, Okabe H, Yano T, Kumamoto T, Suzuki N, Ishikawa T, Ueno K. J. Pharmacol. Sci. 2012; 118: 467

3 Ishikawa T, Hino K, Yoneda T, Murota M, Yamaguchi K, Watanabe T. J. Org. Chem. 1999; 64: 5691
4 Ishikawa T, Watanabe T, Tanigawa H, Saito T, Kotake K.-I, Ohashi Y, Ishii H. J. Org. Chem. 1996; 61: 2774
5 Watanabe T, Oku Y, Ishii H, Ishikawa T. Synlett 1997; 161
6 Ishikawa T, Murota M, Watanabe T, Harayama T, Ishii H. Tetrahedron Lett. 1995; 36: 4269
7 Ishii H, Ishikawa T, Murota M, Aoki Y, Harayama T. J. Chem. Soc., Perkin Trans. 1 1993; 1019
8 Konno F, Ishikawa T, Kawahata M, Yamaguchi K. J. Org. Chem. 2005; 71: 9818
9 Synthetic procedures for compounds shown in Schemes 1 and 2, except those described in Note, are given in Supporting Information.
10 4-Hydroxy-6,7-methylenedioxy-1-tetralone-2-spiro-3′-(6,7-dimethoxyphthalide) (10a) A mixture of 8a (82 mg, 0.223 mmol), NBS (43 mg, 0.243 mmol), and AIBN (5 mg, 0.029 mmol) in dry benzene (8 mL) was stirred at 85 °C for 1.5 h under argon. After addition of EtOAc (30 mL) the solution was washed with H₂O (20 mL) and brine (10 mL), dried over Na₂SO₄, and evaporated. The residual oil was dissolved in THF (10 mL) and H₂O (8 mL). The mixture was stirred at r.t. for 16 h and extracted with CHCl₃ (3 × 20 mL). The combined organic solutions were washed with brine (10 mL), dried over Na₂SO₄, and evaporated. Column chromatography of the residue (SiO₂, toluene–EtOAc = 10:1 → 1:1) afforded trans-10a (24 mg, 28%) as colorless solid, mp 212–213 °C, and cis-10a (27 mg, 31%) as colorless solid, mp 209–211 °C. trans-10a: IR (ATR): 1767, 1682 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.35 (d, J = 7.1 Hz, 1 H, exchangeable), 2.63 (dd, J = 13.7, 9.4 Hz, 1 H), 2.71 (dd, J = 13.7, 4.9 Hz, 1 H), 3.93 (s, 3 H), 4.14 (s, 3 H), 5.36 (ddd, J = 9.4, 7.1, 4.9 Hz, 1 H), 6.09 (s, 2 H), 7.03 (d, J = 8.3 Hz, 1 H), 7.21 (s, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.41 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 43.6, 56.8, 62.4, 64.4, 85.3, 102.2, 106.2, 106.6, 117.1, 117.9, 119.7, 124.2, 141.8, 144.5, 147.9, 148.3, 153.2, 153.7, 167.3, 187.9. MS–FAB: m/z = 407 [M + Na]⁺, 385 [M + H]⁺. Anal. calcd for C₂₀H₁₈O₈: C, 62.50; H, 4.20. Found: C, 62.21; H, 3.96. cis-10a: IR (ATR): 1769, 1684 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.59 (d, J = 9.7 Hz, 1 H, exchangeable), 2.71 (dd, J = 13.6, 7.1 Hz, 1 H), 2.83 (dd, J = 13.6, 5.1 Hz, 1 H), 3.90 (s, 3 H), 4.14 (s, 3 H), 5.16 (ddd, J = 9.7, 7.1, 5.1 Hz, 1 H), 6.11 (s, 2 H), 6.82 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.18 (s, 1 H), 7.43 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 42.2, 56.8, 62.4, 65.5, 84.7, 102.4, 106.7, 107.5, 116.5, 117.9, 119.1, 124.2, 140.2, 142.3, 148.8, 148.9, 153.4, 153.9, 166.5, 188.1. MS–FAB: m/z = 407 [M + Na]⁺, 385 [M + H]⁺. Anal. calcd for C₂₀H₁₈O₈·1/3H₂O: C, 61.54; H, 4.30. Found: C, 61.79; H, 4.11.
11 The same orientation of oxygen functions at the 2- and 4-positions of the tetralone unit is assigned to be cis configuration.
12 2,3-Dimethoxy-6-[2-(1-methoxyimino-6,7-methylene-dioxy-4-oxo-1,4-dihydronaphthyl)]benzoic Acid (1d) A mixture of 11a (230 mg, 0.556 mmol) and IBX (260 mg, 0.929 mmol) in DMSO (4 mL) was stirred at 60 °C for 2 h. After addition of H₂O (10 mL) insoluble precipitate was removed by filtration, and the filtrate was extracted with EtOAc (3 × 20 mL). The combined organic solutions were washed with H₂O (3 × 1 mL) and brine (10 mL), dried over Na₂SO₄, and evaporated. The residue was dissolved in CH₂Cl₂ (20 mL), stirred with Et₃N (0.2 mL, 1.42 mmol) at r.t. for 1 h, and extracted with H₂O (3 × 20 mL). The combined aqueous solutions were acidified with 10% HCl aqueous solution (pH ca. 3) and extracted with CHCl₃ (3 × 20 mL). The combined organic solutions were washed with brine (10 mL), dried over Na₂SO₄, and evaporated. Column chromatography of the residue (SiO₂, acetone–toluene = 1:20) afforded 1d (211 mg, 92%) as pale yellow solid, mp 207–209 °C. IR (ATR): 1725, 1624 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (Z-isomer) = 3.98 (s, 3 H), 3.99 (s, 3 H), 4.03 (s, 3 H), 6.10 (s, 2 H), 6.54 (s, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.68 (s, 1 H), 8.33 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ (Z-isomer) = 55.9, 61.0, 64.4, 102.8, 105.0, 109.2, 113.1, 123.7, 125.8, 127.5, 127.8 (2 C), 130.2, 144.8, 145.2, 149.4, 151.3, 151.4, 153.0, 167.8, 182.1. MS–FAB: m/z = 434 [M + Na]⁺, 412 [M + H]⁺. Anal. calcd for C₂₁H₁₇NO₈: C, 61.31; H, 4.17; N, 3.40. Found: C, 61.14; H, 3.98; N, 3.28.
13 Methyl 2,3-Dimethoxy-6-[2-(1-methoxyimino-6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benzoate (1c) A mixture of 1d (211 mg, 0.512 mmol), MeI (0.07 mL, 1.10 mmol), and K₂CO₃ (140 mg, 1.01 mmol) in DMF (5 mL) was stirred at r.t. for 2 h, diluted with H₂O (10 mL), and extracted with EtOAc (3 × 20 mL). The combined organic solutions were washed with H₂O (2 × 10 mL), sat. NaHCO₃ aqueous solution (5 mL), and brine (10 mL), dried over Na₂SO₄, and evaporated. Column chromatography of the residue (SiO₂, EtOAc–hexane = 1:6 → 1:3) afforded 1c (201 mg, 92%) as pale yellow solid, mp 172–173 °C (lit.^1b mp 171–173 °C). IR (ATR): 1715, 1638 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (Z-isomer) = 3.66 (s, 3 H), 3.93 (s, 2 × 3 H), 4.08 (s, 3 H), 6.12 (s, 2 H), 6.57 (s, 1 H), 7.01 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 7.69 (s, 1 H), 8.33 (s, 1 H). ESI–HRMS: m/z calcd for C₂₂H₁₉NNaO₈: 448.10084; found: 448.10020.
14 Methyl 2-Hydroxy-3-methoxy-6-[2-(1-methoxyimino-6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benz-oate (1f) To a stirred solution of 1c (29 mg, 6.8·10^–2 mmol) in CH₂Cl₂ (7 mL) was added a 1 mol solution of BCl₃ in CH₂Cl₂ (0.14 mL, 7.0·10^–2 mmol) at –78 °C under argon, and the mixture was stirred at the same temperature for 2 h. After addition of H₂O (5 mL) the mixture was extracted with CHCl₃ (3 × 10 mL). The combined organic solutions were washed with brine (5 mL), dried over Na₂SO₄, and evaporated. Purification of the residue by PTLC (CHCl₃) afforded 1f (26 mg, 92%) as yellow solid, mp 154–156 °C. IR (ATR): 2919, 1667, 1634 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (Z-isomer) = 3.60 (s, 3 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 6.13 (s, 2 H), 6.54 (s, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 7.02 (d, J = 8.3 Hz, 1 H), 7.72 (s, 1 H), 8.34 (s, 1 H), 10.8 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ (Z-isomer) = 52.4, 56.1, 64.5, 102.2, 106.2, 109.8, 113.6, 114.2, 120.7, 124.1, 126.8, 128.7, 130.3, 146.3, 148.9, 149.4, 150.0, 151.4, 153.7, 170.7, 183.6. ESI-HRMS: m/z calcd for C₂₁H₁₇NNaO₈: 434.08519; found: 434.08440.
15 Chen J, Zhang Y, Yang L, Zhang X, Liu J, Li L, Zhang H. Tetrahedron 2007; 63: 4266
16 Methyl 4-Hydroxy-5-methoxy-2-[2-(1-methoxyimino-6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benz-oate (1g) A mixture of 16 (7 mg, 1.3·10^–3 mmol), Pd(OAc)₂ (0.15 mg, 7·10^–5 mmol), and Ph₃P (0.7 mg, 2.6·10^–4 mmol) in n-BuOH (3 mL) was stirred at 100 °C for 2 h under nitrogen, diluted with EtOAc (6 mL), and filtered through Celite pad. The filtrate was washed with H₂O (2 × 3 mL) and brine (3 mL), dried over Na₂SO₄, and evaporated. Column chromatography of the residue (SiO₂, EtOAc–hexane = 1:1) afforded 1g (5 mg, 93%) as pale yellow solid, mp 89–91 °C. IR (ATR): 3437, 1771 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ (Z-isomer) = 3.64 (s, 3 H), 3.97 (s, 3 H), 4.00 (s, 3 H), 6.12 (s, 2 H), 6.49 (s, 1 H), 6.91 (s, 1 H), 7.49 (s, 1 H), 7.70 (s, 1 H), 8.35 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ (Z-isomer) = 52.2, 56.4, 64.5, 102.3, 106.4, 110.2, 112.4, 116.6, 123.1, 124.6, 127.3, 129.0, 133.2, 146.1, 146.5, 148.7, 149.5, 151.5, 153.4, 167.1, 183.6. ESI-HRMS: m/z calcd for C₂₁H₁₇NNaO₈: 434.08519; found: 434.08329.
17 Results on the cytotoxic activity of these naphthoquinone oximes will be reported elsewhere.

Zusatzmaterial

Supporting Information